Rosuvastatin, which is an antihyperchlolesterolemic drug, is chemically known as (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid calcium (2:1) salt of Formula I.
Rosuvastatin was for the first time disclosed in U.S. Pat. No. 5,260,440. Rosuvastatin is being marketed under the proprietary name CRESTOR, as an oral tablet, for the treatment of hypercholesterolemia. In view of the importance of Rosuvastatin as a Lipid-lowering agent, several synthetic methods have been reported in the literature to prepare Rosuvastatin, some of which are as summarized below:
U.S. Pat. No. 5,260,440 discloses a process for preparing Rosuvastatin in examples. The process is as shown below:

The difficulties in the above process are that the intermediate (A) is not obtained in pure form readily and its purification is tedious and overall yield is extremely low. Even when intermediate (A) is obtained in pure form, further condensation with intermediate (8) does not result in Rosuvastatin of right quality as the product contains unacceptable level of impurities and further the intermediates are obtained as liquids making it difficult to purify.
WO 2006/076845 Al discloses a process to prepare Rosuvastatin, which comprises nitrilation of pyrimidine aldehyde (11) to give a cyano compound (12) followed by reduction to give 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-mesylamino)pyrimidin-5-propenal (13) and then converted to Rosuvastatin. The process is as shown below:

In this process, nitrilation is carried out using diethylcyanomethyl phosphate. The disadvantage of this process is that during conversion of cyano functionality into aldehyde, lots of impurities are formed along with unwanted cis-isomer, therefore the yield and purity of the product are poor.
WO 03/097614 A2 describes a modified procedure for the preparation of the starting material 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5-pyrimidinecarboxaldehyde and further conversion to Rosuvastatin by condensing with methyl (3R)-3-[(tert-butyldimethylsilyl)oxy]-5-oxo-6-triphenylphosphoranylidene hexanoate. The condensed product was deprotected using methanesulfonic acid and subsequently converted to Rosuvastatin calcium (2:1) salt.
WO 2004/052867 A1 describes a process to prepare Rosuvastatin by condensing 1-cyano-(2S)-2-[(tert-butyldimethylsilyl)oxy]-4-oxo-5-triphenylphosphoranylidene pentane with 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)-5-pyrimidinecarbaldehyde and subsequent deprotection of silyl group, reduction and hydrolysis.
WO 2000/049014 A1 discloses a novel chemical process for the manufacture of tert-butyl-(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-methyl(methylsulfonyl)amino]-pyrimidin-5-yl]vinyl}-(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetate, which comprises reaction of diphenyl {4-(4-fluorophenyl)-6-isopropyl-2-[methyl-(methylsulfonyl)amino]pyrimidin-5-yl-methyl}phosphineoxide with tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate and its further conversion to Rosuvastatin.
WO 2004/014872 A1 describes a process for the manufacture of Rosuvastatin calcium (2:1) salt which comprises mixing a solution of calcium chloride with a solution of water soluble salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid. This process for the preparation of Rosuvastatin employs the use of phosphorane side chain; the preparation of side chain requires eight synthetic steps and involves expensive reagents. The process is both uneconomical and time consuming, hence not appropriate for commercial scale operation.
WO 2006/100689 A1 discloses a process for preparation of Rosuvastatin as shown below:

In the above scheme R1, R2, R3 represent substituted or unsubstituted phenyl and R4 represents an aliphatic residue selected from C1-C4 alkyl, R5 represents C1-C4 alkyl which is optionally substituted by hydroxyl, R6 represents hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy, R7 represents aliphatic residue, R8 represents C1-C4 alkyl.
WO 2006/106526 A1 describes the preparation of Rosuvastatin as shown below:

In the above mentioned scheme R1, R2, R3 are substituted or unsubstituted phenyl and R4 is an aliphatic residue selected from C1-C4 alkyl, R5 represents C1-C4 alkyl, M is an alkali metal salt, X represents a halogen, R6 represents C1-C4 alkyl which is optionally substituted by hydroxyl, R7 represents hydrogen, halogen, C1-C4 alkyl or C1-C4 alkoxy, R8 is an aliphatic residue selected from C1-C4alkyl.
We have now found an improved process to prepare (+)-(3R,5S)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-3,5-dihydroxy-6E-heptenoic acid calcium salt of Formula I that is cost effective and industrially feasible.
Objective
The main objective of the present invention is to provide an improved process for preparing (+)-(3R,5S)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methyl-sulfonylamino)pyrimidin-5-yl]-3,5-dihydroxy-6E-heptenoic acid calcium salt of Formula I.
Yet another objective of the present invention is to provide an improved process for preparing (+)-(3R,5S)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methyl-sulfonylamino)pyrimidin-5-yl]-3,5-dihydroxy-6E-heptenoic acid calcium salt of Formula I, which is simple, industrially applicable and economically viable.